Heparin facilitates the extraction of tissue fibronectin.

Extraction of fibronectin from two human tissues, lung parenchyma and placental villi, was facilitated by the incorporation of heparin into extraction media. The effect of heparin was additive to the effect of urea which is known to extract fibronectin. These experiments provide further evidence that fibronectin and glycosaminoglycans are associated in connective tissues and the use of heparin forms the basis for a simple method for extraction and quantitation of tissue fibronectin.

Serum elastase inhibitor deficiency and alpha 1-antitrypsin deficiency in patients with obstructive emphysema.

A decreased inhibition of pancreatic elastase has been detected in the serums of six patients with alpha(1)-antitrypsin deficiency. Five have severe clinical and physiological pulmonary emphysema. This observation extends the defect of inhibition by serum to a second, biologically active proteolytic enzyme in this form of familial emphysema.

Desmosine as a biomarker of elastin degradation in COPD: current status and future directions.

Desmosine (DES) and isodesmosine (IDES) are two unusual, tetrafunctional, pyridinium ring-containing amino acids involved in elastin cross-linking. Being amino acids unique to mature, cross-linked elastin, they are useful for discriminating peptides derived from elastin breakdown from precursor elastin peptides. According to these features, DES and IDES have been extensively discussed as potentially attractive indicators of elevated lung elastic fibre turnover and markers of the effectiveness of agents with the potential to reduce elastin breakdown. In the present manuscript, immunology-based and separation methods for the evaluation of DES and IDES are discussed, along with studies reporting increased levels of urine excretion in chronic obstructive pulmonary disease (COPD) patients with and without alpha(1)-antitrypsin deficiency. The results of the application of DES and IDES as surrogate end-points in early clinical trials in COPD are also reported. Finally, recent advances in detection techniques, including liquid chromatography tandem mass spectrometry and high-performance capillary electrophoresis with laser-induced fluorescence, are discussed. These techniques allow detection of DES and IDES at very low concentration in body fluids other than urine, such as plasma or sputum, and will help the understanding of whether DES and IDES are potentially useful in monitoring therapeutic intervention in COPD.

The relationship between right duct lymph flow and extravascular lung water in dogs given alpha-naphthylthiourea.

The relationship between right duct lymph flow and extravascular lung water was studied in 3 normal dogs and 15 dogs with pulmonary edema induced by alpha-naphthylthiourea (ANTU). Right duct lymph was collected in a pouch created by ligating jugular, subclavian, and brachiocephalic veins. Extravascular lung water was measured in vivo by double indicator dilution and post-mortem by weighting lungs before and after drying. Cardiac output, pulmonary artery and pulmonary artery wedge pressures, and the concentration of protein and electrolytes in plasma and right duct lymph were determined. Eight lungs were examined by light and electron microscopy. There was a direct relationship between right duct lymph flow (RDLF in milliters per hour per gram dry lung) and extravascular lung water (Qwl in milliliters per gram dry lung) which was best described by the equation RDLF=0.75-0.26 Qwl+0.03 (Qwl).2 Dogs with severe ANTU-induced edema had extensive lung capillary endothelial destruction but only mild interstitial swelling and no visible damage to type I alveolar epithelial cells. Cardiac output, pulmonary artery and wedge pressures, and protein and electrolyte concentrations did not correlate with either extravascular water or right duct flow. Thus, in ANTU-induced pulmonary edema right duct lymph flow was directly related to extravascular lung water with the highest flows occurring with severe edema. The absence of a rapid increase in lymph flow with small increases in extravascular water may be due to early sequestration of fluid in the alveolar space. Hemodynamic changes did not account for changes in lung water or lymph flow. The pulmonary interstitial factors relating increased extravascular water to lymph drainage remain to be determined.

Impaired angiotensin conversion and bradykinin clearance in experimental canine pulmonary emphysema.

Chronic hypoxic lung diseases are associated with abnormal blood pressure regulation. Because the lung is the principal site of angiotensin conversion and because hypoxia decreases converting enzyme activity, we examined whether angiotensin converting enzyme activity was impaired in lung disease. 12 dogs received a 6 wk course of aerosolized and intratracheal papain that produced moderate panlobular emphysema. These dogs and 24 control dogs were anesthetized and sampling catheters were placed under fluoroscopic control. Angiotensin conversion was measured by a blood pressure response bioassay. Pulmonary converting enzyme activity was also assessed by infusing bradykinin (BK) and using radioimmunoassay to measure the instantaneous clearance of BK and the concentration of BK in the pulmonary artery which first produced spillover of BK into left atrial blood. Angiotensin conversion was reduced in the emphysematous dogs to 81.1% (13.2 SD) from 92% (6 SD) in the control dogs (P < 0.01). Instantaneous clearance of BK in the emphysematous dogs was only slightly reduced (93%), despite reduction in their Pao(2) to 75 mm Hg, indicating that the greatest proportion of the perfused vascular bed was exposed to alveolar Po(2) of >90 mm Hg. However, the barrier to BK passage provided by the lung, and measured by the spillover level, was reduced (1/4) to (1/2) that observed in control animals. That the defect was promptly corrected by supplemental oxygen indicates that regional pulmonary vascular converting enzyme activity had been impaired by regional alveolar hypoxia, which permitted some peptide to pass through the lungs unmetabolized. Determination of peptide metabolism in the lungs may provide a useful measure of regional alveolar hypoxia and may lead to new ways of assessing lung injury.

Prevalence of alpha-1 antitrypsin deficiency in poorly controlled asthma--results from the ALA-ACRC low-dose theophylline trial.

In a study comparing low-dose theophylline to montelukast in poorly controlled asthmatics, 285 subjects consented to be screened for alpha-1 antitrypsin deficiency. Of the 284 for which complete data was available, 10.5% carried a deficiency gene and 2.4% were mildly deficient with an alpha-1 antitrypsin serum level of less than 20 mu M. In the non-African-American cohort, an abnormal phenotype occurred in 12% and 2.9% were mildly deficient. Baseline pulmonary function and asthma scores were not significantly different between those with normal and abnormal AAT phenotype. However those with the deficiency tended to show a greater bronchodilator response.

Sustained reversal of chronic hypercapnia in patients with alveolar hypoventilation syndromes. Long-term maintenance with noninvasive nocturnal mechanical ventilation.

Described in this study are eight patients with alveolar hypoventilation syndromes who presented with carbon dioxide narcosis and coma. After reversal of severe hypercapnia, all patients were discharged and maintained at home for an average period of 10 years utilizing "noninvasive" nocturnal mechanical ventilation. The use of "noninvasive" mechanical ventilation at home attempted to void the hazards of tracheostomy and the difficulties inherent in continuous daytime use of oxygen. This form of treatment has allowed these patients to continue their previously productive lives. This study represents the first published long-term follow-up regarding this mode of treatment in patients with alveolar hypoventilation.

Techniques for measuring the responsiveness of the ventilatory apparatus in man in disease.

More complete understanding of the disturbances in the regulation of ventilation in disease must await techniques which can estimate the neural output of the respiratory centers and also the neural inputs. Some of these techniques, such as diaphragmatic electromyography, offer the prospect of clinical usefulness even now and newer techniques, such as mouth occlusion pressure, are promising but have just begun to be evaluated in disease. Despite the limited ability of current techniques to clearly distinguish abnormal central nervous system function of ventilatory control from peripheral mechanical limitations to ventilation, a useful interpretation of clinical tests of ventilatory responsiveness may be gained by an awareness of the many physiologic and pathogenetic factors which are interposed by disease. These factors may reinforce or diminish both stimuli and response. In chronic disease states, these modifying factors must be identified and evaluated for their role in altered ventilatory responsiveness. Frequently, therapeutic measures can induce substantial effects on these modifying factors, whereas primary disturbances of central nervous system function may be difficult to alter. For the above reasons, tests of ventilatory responsiveness which provide information focussed only on the normality or abnormality of responsiveness to CO2 breathing from measurement of minute ventilation and alveolar PCO2 in an unsteady state, as in the CO2 rebreathing test, may, in a patient, require the addition of tests which allow more complete evaluation of these modifying factors. The state of arterial blood gases, hydrogen ion concentration, bicarbonate concentration, pulmonary function, ventilatory response to exercise, as well as understanding of the state of body temperature, catecholamine secretion, the functional state of the muscles of ventilation, as well as the resistances to ventilation are all a necessary part of the evaluation.

What percolation theory can tell us about COPD.

Damage to the lung elastic fiber network is largely responsible for the distention and rupture of alveolar walls in chronic obstructive pulmonary disease (COPD). It has therefore been suggested that blood or urine levels of the unique elastic fiber crosslinks, desmosine and isodesmosine (DID), may serve as a biomarker for the progression of the disease. The prognostic value of DID may be limited, however, by the large degree of variance associated with their measurement in patients with COPD. To overcome this problem, we propose that specific patterns of DID release from damaged elastic fibers, rather than their absolute quantity, may provide a better indication of morphological changes in the lungs of patients with COPD. Using percolation theory to model the elastic fiber network in the lung, it will be shown that the relative amounts of damaged and intact elastic fibers may be reflected at the molecular level by urinary levels of free and peptide-bound DID, respectively. The self-similar nature of percolation networks further suggests that detachment of crosslinks from elastic fibers may be analogous to the rupture of alveolar walls in COPD. Consequently, the ratio of free to bound DID may be a measure of emphysematous changes in this disease.